Use of adenosine antagonists in the treatment of bradyarrhythmias and hemodynamic depression associated with cardiopulmonary resucitation and/or cardiovascular collapse

ABSTRACT

A method to enhance the efficacy of cardioversion, defibrillation, cardiac pacing, and cardiopulmonary resuscitation and to treat post-resuscitation asystole, bradyarrhythmias, electromechanical dissociation, and hemodynamic collapse by administering to a human or animal an effective amount of an adenosine antagonist that competitively inhibits adenosine or that reduces the level of adenosine present in myocardial and vascular tissues and associated fluids.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to the use of adenosine antagonists, either aloneor in combination with pharmacologic possessing α and/or β-adrenergic ordopaminergic properties, to treat cardiac rhythm disturbances,mechanical dysfunction and hypotension and to facilitate cardioversionand/or defibrillation in the setting of cardiopulmonary resuscitationand/or cardiovascular cellapse.

2. Discussion of the Background

Prolonged cardiopulmonary resuscitation for ventricular fibrillation isassociated with the occurrence of asystole or severe bradycardias andprofound hemodynamic collapse associated with a severe depression inmyocardial contractility (electromechanical dissociation) which areusually resistant to therapy. (Rahimtoola S. H., J. Am. Med. Assoc.,247, pages 2485-2890 (1982) and Iseri, L. T., Ann. Int. Med., 8, pages741-745 (1978).)

Catecholamines and/or para-sympatholytic agents have traditionally beenused to treat intractable ventricular fibrillation andpost-defibrillation depressions in automaticity, cardiac conduction, andoverall hemodynamic collapse. However, these agents are oftenineffective, particularly in the setting of prolonged ventricularfibrillation and, as a consequence of their use, may provoke intractableventricular fibrillation followed by death or severe neurologicalimpairment. See McIntyre, K. M., Lewis, A. J., Eds, Textbook of AdvancedLife Support, Vol 9, American Heart Association (1981) and Am. Heart J.,97, 225-228 (1979).

Pharmacological agents are routinely used in the cardiopulmonaryresuscitation of patients suffering from cardiac arrest. A review ofthese pharmacologic agents can be found in Otto C. W., Circ. 74(supplement IV), IV-80-85 (December 1986). It has been established thatthe most significant factor in the return of spontaneous circulationduring cardiopulmonary resuscitation is the enhancement of α-adrenergictone, i.e., an increase in aortic diastolic pressure and coronaryperfusion pressure. However, there has been no suggestion that the useof α-adrenergic agents improve survival relative to the use ofepinephrine, a mixed adrenergic agonist with known deleterious effects.

Additionally, there is no clear evidence that epinephrine, the currentlyrecommended pharmacologic agent, can increase the effectiveness ofelectric shock during the fibrillation.

Lidocaine is the recommended anti-arrhythmic agent for use duringcardiac arrest. It is known however that lidocaine can increase thethreshhold for defibrillation. Under experimental conditions, theanti-arrhythmic drug, Bretylium, seems to facilitate defibrillation;however, clinical data are less convincing. (Jaffe A. S., Circ. 74(supplement IV), IV-70-74, December 1986).

The model established by the present inventors confirms that thecardioversion of prolonged hypoxic ventricular fibrillation isaccompanied by cardiovascular collapse and depressions in cardiacautomaticity, conduction, and contractility. This post-shock hypoxicdepression is due, in part, to the collapse in arteriolar tone possiblymediated by the release of endogenous adenosine. In addition, therelease of endogenous adenosine from myocardium might selectively dilatecoronary resistance vessels promoting hypoperfusion of thesubendocardial layer of the heart, the most distal and thus vulnerablecardiac vascular bed. The result would be enhanced ischemicinduceddepression in contractility. Endogenous catecholamines are known to bereleased with vascular collapse and perhaps in response to an electricalshock. The beneficial vasomotor and inotropic effects of endogenouscatecholamine release may, in turn, be attenuated by the anti-adrenergicaction of endogenous adenosine. The aforementioned potential deleteriouseffects of endogenous adenosine may be reversed by adenosine antagonism.Thus, adenosine antagonism represents an important new therapy in theamelioration of the overall hemodynamic state during cardiopulmonaryresuscitation and following defibrillation and, thus, would be expectedto enhance survival of cardiac arrest victims. This concept has neverbeen proposed.

It is known that endogenous adenosine can depress the electricalconduction through the atrioventricular (A-V) node, and that adenosineantagonism can reverse this phenomenom. U.S. Pat. No. 4,364,922discloses a method of treating atrioventricular conduction block usingadenosine antagonists. However, A-V conduction disturbances play only asmall role in the overall constellation of factors which characterizebrady-asystolic arrest. The more predominant factors noted in theclinical sector include profound bradycardia associated with junctionaland ventricular escape rhythms, and hemodynamic depression secondary tovascular collapse and severe inotropic dysfunction (see Iseri, L.T. etal, loc cit). The use of adenosine antagonism to reverse these phenomenain the setting of prolonged cardiopulmonary resuscitation has never beenproposed.

Accordingly, there exists a need for a more effective pharmacologicmethod of treating the brady-arrhythmias associated with prolongedcardiopulmonary resuscitation. In addition, there exists a further needfor a method of treating these arrhythmias which does not evolve intointractable ventricular fibrillation.

In addition to the aforementioned, the inventors have found thatadenosine antagonism lowers the threshold current required fordefibrillation following prolonged canine ventricular fibrillation andthereby increases the effectiveness of electric shock therapy. Thus, anintravenously administered form of adenosine antagonism may be importantin reducing the duration of ventricular fibrillation, a prognosticfactor known to enhance survival in the setting of cardiac arrest andresuscitation. In addition, an orally administered and longer-actingform of adenosine antagonism may be important in lowering the energy andcurrent requirements of shock therapy administered by implantedelectrodes, increase the efficacy of electric shock, and reduce theenergy expenditure of automatic implantable defibrillators and, thusextending the device's battery life and battery replacement schedule.Adenosine antagonism may also lower the threshold current for cardiacpacing via endocardial and epicardial electrode placement or viatransthoracic pacing electrodes. In addition to intravenous and oralforms, a local sustained release form of adenosine antagonist may beincorporated into the electrode tips of endocardial and epicardial leadsfor the purpose of lowering pacing thresholds.

At present there are no claims in the medical literature divulging theuse of adenosine antagonism to lower energy and current requirements forcardio-version, defibrillation, and cardiac pacing. Kralios et al (AmHeart J: 105(4): 580-586) infused exogenous adenosine into caninecoronary arteries and demonstrated a reduction in the threshold currentnecessary to induce ventricular fibrillation. However, the authorsconclude "physiologic or pharmacologic coronary vasodilation withoutevidence of concomitant myocardial hypoxia" may contribute to theelectrical instability resulting in ventricular fibrillation. No claimwas made that the release of endogenous adenosine during the conditionsof anoxia or hypoxia mediated such electrical instability or thatantagonism of endogenously released adenosine would promote ventriculardefibrillation. Ruffy et al (J. Am. Coll. Cardiology 9(2): l42A, 1987)showed that aminophylline (10 mg/Kg IV) lowered defibrillation thresholdin conscious dogs. However, defibrillation energy is a poor descriptorof the electrical requirement for defibrillation compared to current(Lerman et al. J. Clin. Invest. 80: 797-803, 1987). Aminophylline is arelatively weak adenosine antagonist with well established effects onphosphodiesterase inhibition. The authors did not correlate effects ondefibrillation threshold with serum levels of aminophylline. At a doseof 10 mg/Kg, the authors could not and did not claim that the effect ofaminophylline was mediated via adenosine antagonism.

Additionally, the inventors have demonstrated in a pentobarbitalanesthetized dog that 8-phenylsulfonyltheophylline (8-PST) (5 mg/Kg IV)significantly reduced the number of current-based countershocks requiredto terminate ventricular fibrillation of 2 mins. duration. In contrastto aminophylline, 8-PST is highly specific for competitive adenosineantagonism and causes no significant inhibition of phosphodiesteraseactivity (Clemo, SHF and L Belardinelli, 1985). A comparative study ofantagonism by alkylxanthines on the negative dromotropic effect ofadenosine and hypoxia in isolated guinea-pig hearts is disclosed inCurrent Clinical Practice Series No. 19: Anti-asthma Xanthines andAdenosine, K. E. Anderson and C. Kong, Princeton, Sydney, Tokyo, pp.417-422; and F. W. Smellie, C. W. Davis, J. W. Daly, and J. N. Wells,1979. Alkylxanthine inhibition of adenosine-elicited accumulation ofcyclic AMP in brain slices and of brain phosphodiesterase activity isdisclosed in Life Sci. 24:2475-2482. Thus, we claim that the observedeffect is mediated by adenosine antagonsim and is consistent with ourother experimental observations. Since no convincing clinical data existestablishing the efficacy of presently available pharmacologic agents inreducing threshold currents for defibrillation, we propose that thereexists a need for such an agent.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide a methodof treating post-resuscitation bradyarrhythmias, hemodynamic collapse,and electro-mechanical dissociation associated with prolongedcardiopulmonary resuscitation.

Another object of the invention is to provide a method of treatingbradyarrhythmias, hemodynamic depression, and contractile dysfunctionassociated with hypoxemia needs as might occurred during cardiovascularcollapse e.g. of cardiogenic, septic, hypovolemic or hemorrhagic shock).

A further object of the invention is to promote the efficiency ofcardiopulmonary resuscitation itself by altering the potentialdeleterious vasomotor effect of endogenously released adenosine. Theinvention thus promotes the maintenance of aortic diastolic pressure andcoronary perfusion pressure and reverses harmful hypoperfusion of thesubendocardium mediated by an adenosine-induced coronary "steal"phenomenon.

A further object of the invention is to provide a pharmacologic methodfor lowering the threshold current and energy for defibrillation thusenhancing the efficacy of defibrillation and/or cardioversion. Onemechanism whereby this is accomplished is by favorably alteringperipheral and cardiac vasomotor tone.

Another object of the invention is to provide a pharmacologic method forlowering the current and energy requirements for cardiac pacing (viatransthoracic, epicardial, or endocardial electrodes) in the setting ofresuscitation.

A further object of the invention is to provide a method of preventingand/or treating post-resuscitation asystole and bradyarrhythmias byusing a pharmacologic agent which lowers the threshhold fordefibrillation and thus, shorten the duration of ventricularfibrillation.

A further object of the invention is to provide a method preventingand/or (treating of post-resuscitation arrhythmias with adenosineantagonists.

These and other objects of the present invention which will becomeapparent from the following detailed description have been achieved bythe present method, comprising this step of:

administering to a human or animal during or after cardiopulmonaryresuscitation and/or cardiovascular collapse an amount of an adenosineantagonist sufficient to alleviate post-resuscitation bradyarrhythmiasand hemodynamic collapse.

Note these aforementioned objects and methods are proposed for potentialuse either alone or in combination with α- and/or β-adrenergic ordopaminergic agents with the possibility of lowering doses required andavoiding potential dose-dependent side-effects while maintaining orenhancing efficacy.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 illustrate of intravenous 8-PST (5 mg/Kg) infusion on canine postdefibrillation heart rate and rhythm (Group A). Panel A: Sinus arrestand junctional rhythm (cycle length =2880 msecs) prior to 8-PSTinfusion. Panel B: Sinus rhythm (cycle length =1240 msecs) at 15 secs,after rapid 8-PST infusion;

FIG. 2 illustrates the lack of effect of ventilation alone followingcanine cardiac defibrillation. Following defibrillation (3rd shock at 44A), idioventricular rhythm (cycle length =4360 msecs; blood pressure=28/26 mmHg) appears. Ventilation alone had no effect on heart rate orblood pressure;

FIG. 3 illustrates the effect of 8-PST (5 mg/Kg) pre-treatment on caninepost-defibrillation blood pressure. After defibrillation (35A) at 2minutes, 2:1 AV block appears transiently, followed by sinus rhythm anda marked overshoot in blood pressure. Ventillation has not beenre-initiated;

FIG. 4 illustrates 4-DPPC induced attenuation of porcineelectrophysiologic depression following First (FSC) and Second ShockConversions (SSC). Panel A: FSC -- control. The sinus cycle length (SCL)at the 10th beat equals 500 msecs., and the PR interval equals 160msecs. Panel B: FSC - Post 4-DPPC. At the 10th beat, the SCL and PRintervals are 360 and 120 msecs, respectively. Panel C: SSC control.Transient complete atrioventricular (AV) block is followed by 2:1 AVblock at 15 secs post-defibrillation. Panel D: SSC - Post 4-DPPC. AVblock is prevented. At the 10th beat, the SCL and PR intervals are 400and 120 msecs, respectively;

FIG. 5 illustrates the complete atrioventricular (AV) block in a porcineheart the absence of an escape rhythm following a Second ShockConversion (SSC): Reversal by 4-DPPC. Panel A: SSC - control. Note thatthere is no ventricular depolarization within the first 15 secs.post-defibrillation. At the 10th p-wave, the SCL equals 520 msecs. PanelB: SSC - post 4-DPPC. Only transient AV block is noted within the first2 secs. At the 10th beat, the SCL and PR intervals are 400 and 120 msecs, respectively;

FIG. 6 illustrates the reversal of porcine post-defibrillationelectrophysiologic and hemodynamic depression by 4-DPPC in the presenceof dipyridamole. Panels A and C display post-shock sequelae following 45secs of ventricular fibrillation (VF) after the intravaneous infusion ofdipyridamole (6.5 mg) during concomitant infusion of methoxamine 0.015mg kg⁻¹ min⁻¹.

40A shocks were delivered at the arrows. Panel A: Effect ofDipyridamole. Complete atrioventricular (AV) block without an escaperhythm is displayed. The aortic pressure (AoP) at the end of 15 secs was20 mmHg. Panel B: Reversal of depression following 4-DPPC injection.4-DPPC (5 mg kg⁻¹) is injected prior to beginning of the panel (30 secspost-defibrillation). Chest compression is initiated for less than 30secs. At the rightward panel, the sinus cycle length SCL and AoP were400 msecs and 125/95 mmHg, respectively. Panel C: Prevention ofdepression after 4-DPPC pretreatment. Following defibrillation,transient 3:1 block gives way to sinus rhythm and an AoP of 125/90 mmHgat 15 secs post-defibrillation. Short episodes of ventricular begeminyand nonsustained ventricular tachycardia were noted at the end of thetracing; and

FIG. 7 illustrates the reversal of porcine Post-defibrillationelectrophysiologic and hemodynamic depression by 4-DPPC in the presenceof dipyridamole. Panels A and C display post-shock sequelae following 45secs. of ventricular fibrillation (VF) after the intraveneous infusionof dipyridamole (1.5 mg) during concomitant infusion of methoxamine,0.015 mg kg⁻¹ min⁻¹. 40A shocks were delivered at the arrows. Panel A:Effect of dipyridamole. Initial 3:1 atrioventricular (AV) block isfollowed by 2:1 AV block and an aortic pressure (AoP) of 70/30 mmHg at15 secs post-fibrillation. Panel B: Reversal of depression following4-DPPC injection. 4-DPPC (5 mg kg⁻¹ IV) is injected prior to thebeginning of the panel (30 secs post-defibrillation. The AoP had fallento 60/25 mmHg. Post-injection in the absence of chest compression, theAoP rises to 125/95 mmHg, and the sinus cycle length (SCL) equals 410msecs at the end of the cycle. Panel C: Prevention of depression after4-DPPC pretreatment. Fifteen seconds after defibrillation transient 3:1AV block has been supplanted by sinus rhythm (SCL, 400 msecs) and an AoPof 125/90 mmHg.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention has succeeded in providing a method for thetreatment of post-resuscitation brady-arrhythmias and hemodynamiccollapse associated with prolonged cardiopulmonary resuscitation fromventricular fibrillation and/or cardiac arrest. The inventors havediscovered that endogenous adenosine not only depresses theatrioventricular (AV) nodal conduction but also is associated with thepost-shock hypoxic depression of automaticity, contractility andhypotension of heart muscle. It has also been discovered that adenosineantagonism can reverse such depression and restore normalelectrophysiologic and hemodynamic function in a short period of time.Thus, the invention involves the use of an adenosine antagonist, eitheralone or in combination with pharamacologic agents possessing α- and/orβ-adrenergic or dopaminergic properties, to treat cardiac rhythmdisturbances, mechanical dysfunction and hypotension and to facilitatecardioversion and/or defibrillation during and/or after cardiopulmonaryresuscitation.

By "adenosine, antagonists" is meant any agent which acts by whatevermechanism to reduce the effect or the interstial concentration ofadenosine in myocardial tissue. An antagonist of adenosine may be acompetitive inhibitor or a substance that reduces the concentration ofadenosine by destroying adenosine or that causes its destruction byaltering metabolic pathways normally present in cells or extracellularfluid. An irreversal inhibitor is not suitable for the present inventionsince the action of adenosine performing its inherent regulatoryfunctions must not be permenantly impaired. Examples of known adenosineantagonists are the xanthines, alkylxanthines, for example,propylxanthines and methylxanthines (e.g.,8-(p-sulfophenyl)theophylline) and the novel non-xanthine adenosineantagonists (e.g., imidazopyrimidine, pyrazolopyridine, etazolate,pyrazoloquinoline, and triazoloquinazoline (Pflugers Archiv 407: S31,1986).

Preferred examples of methylxanthines are 1,3,7-trimethylxanthine(caffeine); 3,7-dimethylxanthine (theobromine); 1,3-dimethylxanthine(theophylline); aminophylline; and the xanthine derivatives disclosed inthe specification of U.S. Pat. No. 4,364,922 incorporated herein byreference. Preferred propylxanthines are(E)-4-(1,2,3,6-tetrahydro-l,3-dimethyl-2,6-dioxo-9H-purin-8-yl)cinnamicacid and(E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-l,3,dipropyl-9H-purin-8-yl)cinnamicacid. The method of synthesizing the xanthine is not critical and can beperformed by any known method of synthesizing these compounds, forexample, the method disclosed in U.S. Pat. No. 4,364,922.

(E)-4-(1,2,3,6-tetrahydro-l,3-dimethyl-2,6-dioxo-9H-purin-8-yl)cinnamicacid and the corresponding dipropyl derivative whose structures areshown below may be synthesized from the corresponding uracil andformylcinnamic acid compounds. ##STR1##

The method of the present invention relates to the enhancement of theefficacy of cardiopulmonary resuscitation and to the treatment ofpost-resuscitation asystole, bradyarrhythmias, electro-mechanicaldissociation, and hemodynamic collapse. The method also relates to thelowering of energy and current requirements for defibrillation,cardioversion, and cardiac pacing in the setting of resuscitation.

The adenosine antagonists used in the present method may be used aloneor in combination with agents possessing α- and/or β-adrenergic ordopaminergic properties. Preferred examples of α-adrenergic agents areepinephrine, norepinephrine, phenylephrine, metaraminol, andmethoxamine. Preferred examples of β-adrenergic agents are epinephrine,norepinephrine, and isoproterenol. Preferred examples of dopaminergicagents are dopamine and dobutamine.

Dosages of the adenosine antagonists for treating post-resuscitationcardiac arrhythmias fall within the range of 0.1-20 mg/kg. An effectivedose may be recognized by the alleviation of bradycardia and reversal ofhemodynamic collapse.

Standard procedures for administration of adenosine antagonists such astheophylline and aminophylline at effective dosage levels are wellestablished and are well known to those skilled in the art. For example,the recommended therapeutic range for plasma levels of theophylline forpatients with reversible obstruction of the airways is from 10-20 μg/ml.

Similar plasma levels are suggested above for the treatment of theresuscitation and post-resuscitation state. These plasma levels may beestablished by standard methods of administration, including but notlimited to intravenous injection, oral injestion via tablets, capsules,or liquids, suppository implantation, intramuscular injection,inhalation and the local release from implanted electrodes. Any of thesemethods, which are able to provide the proper plasma level are suitablefor the present invention. The locally released preparations would notrequire systemic concentrations or effects to obtain the desired ac ionof optimizing electrode efficacy. The preferred method of adminstrationis intravenous injection for resuscitation and post-resuscitationstates. Intravenous administration of the adenosine antagonists and/orα-adrenergic or β-adrenergic or dopaminergic agents may consist of asingle injection, a loading dose followed by continuous administrationof the lower level maintenance dose, injection spaced over a period oftime, continuous injection of a low level maintenance dose, injectionspaced over a period of time, continuous injection of a low levelmaintenance dose, or other types of administration that are suitable forthe particular needs of the individual human or animal being treated.Dosages of theophylline and aminophylline required for specific plasmalevels are well known to those in the art, as shown in the article"Rational Intravenous Dosages of Aminophylline" by Mitenko and Ogilvie,New England J. Med., 289, pages 600-603 (1973). For example, to achievea theophylline plasma level of 10 μg/ml , theophylline is administeredin an initial loading dose of 5-6 mg/kg followed by a continuousmaintenance dose of 0.90 mg/kg/hr.

Administration of these amounts is-sufficient for achieving andmaintaining a plasma level of 10 μg/ml for any method in whichtheophylline or a derivative is absorbed into the blood stream withoutbeing destroyed. Nonlimiting examples include intravenous injection,absorption by the large intestine from suppositories, absorption by thesmall intestine from capsules that release theophylline or otheradenosine antagonists in the intestine after passing through thestomach, or absorption through the lungs. Methods that require theadenosine antagonists to pass through the stomach may be subject todestruction of the antagonists and accordingly must be either protectedin a form that is not destroyed in the stomach or administered in alarge dose so that the amount reaching the blood stream is sufficient toachieve the desired effective level.

When the adenosine antagonists is administered with an α-adrenergic orβ-adrenergic or dopaminergic agent, the relative ratio of these twocomponents should be in the range of 0.01:1.0 to about 1.0:0.01.

The pharmaceutical compositions of the present invention may contain oneor more adenosine antagonists as well as one or more α-adrenergic and/orβ-adrenergic or dopaminergic agents. The pharmaceutical preparations maybe prepared in any of the customary methods well known in the art.

The adenosine antagonists may be admixed with any pharmaceuticallyacceptable carrier or carriers, such as water, ethanol, inert solids orany other carrier customarily used for the type of administration inquestion.

The method of the present invention may be used in the treatment ofhumans and in the practice of veterinary medicine on warm bloodedmammals. Examples of mammals which may be treated include cats, dogs,horses, etc.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES EXAMPLE 1 Preparation of(E)-4-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purin-8-yl) cinnamicacid (4-DMPC)

5,6-Diamino-l,3-dimethyluracil hydrate (1.70 g, 10.0 mmol) and4-formylcinnamic acid (1.76 g, 10.0 mmol) were refluxed in acetic acid(10 mL)-methanol (100 mL) for 0.5 hour.(E)-4[(6-Amino-l,2,3-4-tetrahydro-1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)iminomethyl]cinnamicacid was precipitated as a yellow powder (1.84 g, 56%); mp 299°-301° C.with effervescence. Analysis for (C₁₆ H₁₆ N₄ O₄): C,58.53;H,491;N,1707.Found: C,58.36;H,4.93;N,16.90. The structure was confirmed by H-NMR andEI mass spectrum. The(E)-4-[(6-amino-1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxo-5-pyrimidinylmethyl]cinnamicacid (500 mg, 1.52 mmol) was then refluxed in nitrobenzene (125 mL) for2.5 hours with slow distillation to remove water formed. The reactionmixture was cooled and the precipitate washed with ether.Recrystallization from N,N-dimethylformamide-water gave the monohydrateof the title compound as a pale yellow powder; mp>380° C. Analysis for(C₁₆ H₁₄ N₄ O₄ H₂ O):C, 55.81; H, 4.68; N, 16.27. Found: C, 56.05: H,4.69; N, 16.27. The structure was confirmed by ¹ H-NMR and EI massspectrum.

Alternatively, the 1,3-dimethylxanthyl cinnamic acid can be prepared byreflexing 5,6-diamino-l,3-dimethyluracil hydrate (5.11 g, 30.0 mmol) and4-formylcinnamic acid (5.29 g, 30.0 mmol) in nitrobenzene (500 mL). Thenitrobenzene was allowed to distill slowly with water formed. Freshnitrobenzene was added to keep the volume constant. After 5 hours ofreflux, the mixture was cooled and the precipitate collected (8.07 g).Recrystallization from N,N-dimethylformamide-water gave the monohydrateas a pale yellow powder, identical with that prepared by the methoddescribed above by ¹ H-NMR and elemental analysis.

EXAMPLE 2 Preparation of(E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-l,3-dipropyl-9H-purin-8-yl) cinnamicacid (4-DPPC)

(E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-l,3-dipropyl-9H-purine-8-yl)cinnamicacid was prepared by following an analogous procedure to that forpreparing the 1,3-dimethylxanthyl cinnamic acid. The 1,3-dipropylcompound was prepared with a melting point of 355° C. (dec.).

Analysis for (C₂₀ H₂₂ N₄ O₄) C, 62.82; H, 5.80; N, 14.65. Found: C,62.91; H, 5.84; N, 14.63.

Testing Procedure I:

Mongrel dogs weighing 20 to 26 Kg were anesthetized with intravenoussodium pentobarbital (25-30 mg/Kg), intubated, and mechanicallyventilated at a rate sufficient to maintain PaCO₂ at 35 to 45 mmHg andpH between 7.35 and 7.45. The right femoral artery was cannulated fordetermination of arterial blood pressure. ECG lead II was continuouslymonitored. VF was induced by low voltage alternating current through a 6Fr bipolar electrode catheter introduced into the right carotid arteryand advanced into the left ventricle. The cessation of ventilation andclamping of the endotracheal tube preceded each induction of VF.Defibrillatory shocks of damped sinusoidal waveforms were administeredwith a Physio Control Lifepak 6 defibrillator via an apparatus whichmaintained balance and constant pressure of thoracic electrodes (50newtons). A 6 Fr angiographic catheter was introduced into the rightexternal jugular vein and advanced to the right atrium for purposes ofdrug administration. Rapid bolus infusions of 8-PST (5 mg/Kg⁻¹) wereadministered intravenously.

Protocols

Prior to the experiments designed to elucidate the efficacy of adenosineantagonism, the threshold current for defibrillation was determined bydelivering sequential incremental DC shocks for VF lasting less than 45seconds. No depression of automaticity, conduction, or hemodynamic statewas noted (FIG. 1). The current was measured in a storage oscilloscopefor the waveform generated across a current sensitive resistor in serieswith a voltage divider network with known applied voltage. Duringsubsequent experimentation, all shocks were administered with a peakcurrent of 35 Amps (A) on the first two shocks and at 40 to 50 A on allsubsequent shocks.

Experiments were divided into two groups of dogs; that is, Group Acontrol dogs (no pre-treatment) and Group B dogs were pre-treated with8-PST. In both groups, closed chest massage was not performed and DCshocks were initiated following 2 minutes of VF. In Group A, followingdefibrillation 8-PST was infused after marked bradycardia andhemodynamic collapse had developed. In a subset of dogs, ventilation wasperformed prior to 8-PST infusion. In Group B, the dogs were pre-treatedwith 8-PST (5 mg/Kg IV) 2 to 5 minutes before the induction of VF.Following defibrillation, if hemodynamic collapse persisted, ventilationwithout closed chest massage and/or a subsequent infusion of 8-PST wasadministered. Ventilation was routinely initiated following hemodynamicrecovery.

Statistical analysis of variables was based on the Student'st-distribution for paired and unpaired data (15). Significant differencewas considered for p<0.05. All values were expressed as the mean±standard error of the mean (SEM).

Results

Dogs pre-treated with 8-PST (Group B) required significantly fewercountershocks (1.3±0.2; n =8) versus Group A (2.5±0.6; n =9), p <0.05)even though the pretest ventricular defibrillation threshold (VDT) forVF less than 45 seconds for Group A (23.2±1.2 A) and Group B (25.5±2.1A) were similar. No dog in Group B required more than two shocks of 35 Ato defibrillate. The duration of VF was significantly different for thetwo groups (157±25 secs for Group A and 125±3 secs for Group B; p<0.05).

In Group B, the post-defibrillation ventricular cycle length (583±47msec; n =8) was only slightly different from the pre-8-PST (395±29 msec;n =8) and pre-VF (397±29 msec; n =8) cycle lengths. While transient AVblock was seen immediately post-defibrillation, 6 of 8 animals fromGroup B exhibited sinus rhythm within 10 seconds followingdefibrillation. In contrast, severe bradycardia was notedpost-defibrillation in Group A animals with 5 of 9 animals exhibitinghigh grade AV block, idioventricular and idionodal rhythms. The meanpost-defibrillation ventricular cycle length for Group A was 2428±516msec, n =9. Subsequent infusions of 8-PST, however, restored sinusrhythm in 4 of these 5 animals and reversed bradycardia in 7 of 9animals shortening the post-defibrillation cycle length to 940±63 msecs.(FIG. 1.)

No animal from Group A exhibited hemodynamic recovery. Thepost-defibrillation pre-intervention blood pressure in Group A equalled22±3/17 ±2 mmHg, n =9. Immediately after defibrillation, ventilation hadno effect on blood pressure and failed to promote hemodynamic recovery.(FIG. 2.)

Most notably, pre-treatment with 8-PST (Group B) significantly improvedthe post-defibrillation hemodynamic state with 6 of 8 animals exhibitingcomplete recovery. Two of six required no interventions. (FIG. 3.) Twoothers recovered following the onset of ventilation while two requiredin addition a second bolus infusion of 8-PST. Prior to VF, 8-PSTinfusion had had no significant effect on blood pressure or heart rate.

The 6 animals with complete hemodynamic recovery displayed a markedovershoot in blood pressure (227±14/108±12 mmHg) which later reduced to141±5/97±5 mmHg, approximating the pre-VF values (156±11/101±3 mmHg). Inthe 4 animals requiring ventilation and/or a second infusion of 8-PST,the post-defibrillation pre-intervention blood pressure equalled53±6/26±4 mmHg. In the two animals which failed to recover despiteintervention, the post-defibrillation, pre-intervention blood pressureaveraged 28/24 mmHg. Of interest, no animal from Group B refibrillatedafter prior conversion of VF.

Only two animals in Group B required more than one countershock (i.e., 2shocks) to defibrillate in 3 episodes of VF. The mean duration of VF inthese animals was 137±4 secs., and the mean post-defibrillation,pre-intervention blood pressure was 105±57/51±20. Both recovered. Of the3 animals from Group A which required 2 countershocks to defibrillate,the mean duration of VF was comparable (146±4 secs), but the meanpost-defibrillation, pre-intervention blood pressure measuredsignificantly less (23±2/19±3 mmHg; p <0.05).

Two of nine animals from Group A, and 6 of 8 animals from Group Brequired one shock to defibrillate and thus had comparable VF durations(120 secs). The mean post-defibrillation, pre-intervention bloodpressures for Groups A and B were significantly different (36±3/25±0mmHg versus 81.0±35/ 43±18 mmHg respectively, p <0.05).

Two of nine animals from Group A, and 6 of 8 animals from Group Brequired one shock to defibrillate and thus had comparable VF durations(120 secs). The mean post-defibrillation, pre-intervention bloodpressures for Groups A and B were significantly different (36±3/25±0mmHg versus 81.0±35/ 43±18 mmHg respectively, p <0.05).

Testing Procedure II:

Domestic pigs of either sex weighing 45 to 55 pounds were intubatedfollowing mask induction with 3% halothane and supplemental intravenoussurital and subsequently maintained on an inhaled anesthetic regimen of0.3 to 0.6% halothane and a 1:1 mixture of oxygen and nitrous oxide.This anesthetic regimen has previously been used in the testing ofdefibrillation threshold in a porcine model (1). The lowest dose ofhalothane that maintained the mean aortic pressure greater than 90 mmHgin the absence of corneal reflexes was used. Ventilation via a Harvardrespirator (model 944, Harvard Apparatus, South Natick, MA) was adjustedto maintain arterial pH and pCO₂ between 7.35 to 7.45 and 35 to 45 mmHgrespectively. Fluid-filled angiographic catheters were advanced in theright femoral artery and right internal jugular veins for measurement ofdescending aortic and right atrial pressures respectively.Electrocardiographic lead II and pressures (Statham P23Db transducer,Statham Instruments, Inc., Oxnard, CA) were continuously monitored on anelectrostatic recorder (Model 7758A, Hewlett-Packard, McMinnville, OR).A thermodilution Swan-Ganz catheter was advanced through the rightfemoral vein into the inferior vena cava for drug infusion andcontinuous measurement of central core temperature. New self-adherent R2pads (Model 410, R2 Corporation, Morton Grove, IL) were firmly attachedover the shaven right and left lateral thoracic walls at the transverselevel of the heart and secured with an Ace Bandage.

Ventricular fibrillation (VF) was induced by applying alternatingcurrent through a percutaneous quadripolar catheter (No. 6F, UnitedStates Catheter and Instrument Corp., Billerica, MA) positioned in theright ventricle. The endotracheal tube was automatically clamped atpeak-inspiration via a solenoid-switch at the induction of VF.Damped-sinusoidal DC shocks wee delivered by a commercially-availabledefibrillator (Model 43l00A, Hewlett-Packard, McMinnville, OR)calibrated to deliver 3,000 V at 400 J across a 50 0 Ω load which wasmodified for prospective delivery of current through a constant-loadcurrent divider circuit as described by Lerman et al. (2). A rhythmstrip of 15 secs duration was automatically produced with eachdefibrillation attempt. Voltage delivered across the thorax was measuredwith a 1,000:1 voltage divider in parallel with the defibrillatoroutput, and the delivered current was measured with a 0.10 Ω resistor inseries with the defibrillator output. Voltage and current waveforms weredisplayed on a triggered-sweep storage oscilloscope (Model 5113,Tektronix, Beaverton, OR) with a frequency response from DC to 1 MHz.Prior to defibrillation trials, transthoracic impedance was calculatedfrom delivered energy and current following a synchronized DC shock atapproximately 20 A during sinus rhythm. During the performance of eachprotocol, the variable resistors were then adjusted to deliver thedesired current to the animal and simultaneously maintain a constant 500 load to the defibrillator. Thus, a slightly overdamped pulse wasdelivered (that was within 2% of the selected current) during eachdefibrillation trial, regardless of the transthoracic impedance.

Statistical Analysis. Statistical analysis of variables was based onstudent's t-distribution for paired and unpaired data (3). Significantdifference was considered for p-values less than 0.05. All values wereexpressed as the mean ±standard error of the mean (SEM).

PROTOCOL NO. 1:

The objective of this protocol was to determine the effect of 4-DPPC onpost-defibrillation rhythm disturbances associated with multiplerepetitive ventricular fibrillation (VF) episodes. Temperature rangedfrom 33.5° to 35.5° C. for the protective effect of mild hypothermia onventricular function. Temperature varied by no more than 1° C. in agiven animal. Following the initial determination of transthoracicimpedance, each animal was subjected to VF of 15 secs duration followedby a DC shock at 36A. Thereafter, following sequential 7.5 min recoveryperiods, VF episodes of 15 secs duration were followed by defibrillatoryattempts at 2 A decrements until an initial shock failed. Upon thefailure of any initial shock, ventilation and manual sternal compressionat 80/min were initiated, followed by a rescue shock at 40 A, which wasdelivered at 26 to 30 secs of total VF duration. Subsequent testing wascharacterized by a 1 A increment following a precedent failure, and by a1 A decrement following a precedent success. Basal thresholdrequirements (i.e., current-based defibrillation thresholds (DFT)) weredetermined by averaging the current values of at least 3 successfulinitial shocks which were followed by episodes demonstrating initialshock failures. After the basal DFT had been determined, either placeboor 4-DPPC (5 mg.kg⁻¹ dissolved in an alkalinized saline solution of pH11.0 at a concentration of 2 mg/cc) was administered intravenously, andtesting was continued with post-intervention threshold requirementsdetermined as above.

PROTOCOL NO. 2:

The objectives of this protocol were to determine whether 4-DPPC couldreverse post-defibrillation bradycardia and hemodynamic depression notedin the presence of dipyridamole, an adenosine-uptake blocker.Temperature ranged from 36° to 37° C. in all animals. In order tocounter the undesirable hypotensive actions of dipyridamole (BoerhingerIngelheim) and methoxamine (Burroughs-Wellcome Co.) at 0.015mg.kg⁻¹.min⁻¹ IV were infused intravenously. After 10 minutes ofmethoxamine infusion, intravenous dipyridamole was administered assequential 0.5 mg boluses at 30 to 60-second intervals until bloodpressure returned to premethoxamine levels. VR of 45 secs duration wasinitiated followed by a DC shock at 40 A. Post-shock sequelae (rhythmdisturbances and hemodynamic depression) were observed withoutintervention for 30 seconds. If systolic pressure equalled or exceeded40 mmHg, a rapid intravenous bolus of 4-DPPC (5 mg.kg.⁻¹) was injectedand the response noted. If systolic pressure was less than 40 mmHg,4-DPPC was infused followed by no more then 30 secs of chestcompression, which was performed to promote drug delivery. Afterrecovery (7.5 minutes), additional intravenous dipyridamole (2 to 3 mg)was administered in divided doses to demonstrate continued antagonism ofdipyridamole's hypotensive effect. A second VF episode of 45 secsduration was then repeated, followed by DC shock at 40 A.

RESULTS OF PROTOCOL NO. 1:

4-DPPC failed to significantly reduce DFT when compared to placebo(Table 1). Thus, an effect of adenosine antagonsim on defibrillationthreshold may not be present with short ventricular fibrillationdurations as endogenous adenosine release may be insuficient to altercurrent requirements. In contrast, 4-DPPC substantially reversedpost-defibrillation depression of sinus node (SN) automaticity andatrioventricular (AV) nodal conduction (FIG. 4; Table 2). For example,with regard to first shock conversions (FSC), 4-DPPC significantlyreduced the PR interval (102.5 ± 2.5 msec vs 143.8±9.0 msec, N=5, p=0.012) and sinus cycle length (360.0±8.2 msec vs 447.5±9.5 msec, N=5, p=0.003) compared to control when intervals at the 10th beat followingsuccessful defibrillation were analyzed.

The effect of 4-DPPC on reversing A-V nodal conduction disturbances wasmore pronounced when a second DC shock was required, i.e. for secondshock conversions (SSC) (FIG. 4,5; Table 2). In 47% (9 of 19) of controlSSC episodes, less than 10 beats were noted in the first 15 secs. Ofthese 9 episodes, 7 exhibited high-grade (>2:1) AV block and theremaining two displayed complete AV block without ventricular captureduring the first 15 secs post-defibrillation (FIG. 5). By contrast, inthe presence of 4-DPPC no SCC episode exhibited less than 10 beatsduring the first 15 secs after defibrillation, and in only one of 16episodes was a rhythm other than sinus (i.e. 2:1 AV block) noted at the10th beat. 4-DPPC significantly increased the number of beats observedin the first 15 secs after defibrillation and significantly reduced PRinterval and SCL in the 15 of 16 episodes in which sinus rhythm waspresent at a 10th beat (Table 1). In addition, the mean cycle length ofthe first 3 beats post-defibrillation was significantly shorter after4-DPPC (Table 1).

PROTOCOL NO. 2:

Methoxamine infusion significantly increased sinus cycle length (SCL)and aortic pressures prior to the administration of dipyridamole (Table2). In response to dipyrimadole (1.5 to 7.5 mg), blood pressure returnedto pre-methoxamine levels; however, SCL singificantly lengthenedfurther. During the first defibrillation period following dipyridamoleadministration (post VFl), the average heart rate and blood pressureduring the first 15 secs after defibrillation were 30% and 50% lesscompared to 4-DPPC pretreatment values (post VF2) respectively (Table2). In response to rapid infusions of 4-DPPC during the firstpost-defibrillation period (post VFl), both heart rate and aorticpressure rose markedly within 30 seconds post-injection (FIGS. 6, 7;Table 3). In 3 of 5 experiments, reversal of post-defibrillationhemodynamic collapse after 4-DPPC injection occured during concomitantmanual chest compression that was performed to facilitate drug deliverybecause of inadequate pulse pressure (i.e. systolic pressure <40 mmHg).However, in two other instances, when pulse pressure was adequate fordrup delivery (i.e. systolic pressure >40 mmHg), 4-DPPC also reversedhemodynamic collapse. In one instance, this occurred following a furtherdeterioration in blood pressure (FIG. 7), and in another after priorinjection of an equivalent volume of 4-DPPC diluent (placebo) haddemonstrated no effect. Overall in 2 cases tested, an equivalent volumeof placebo (i.e., 4-DPPC diluent) had no effect on post-defibrillationheart rate or blood pressure. Prior to the second episode of VF (VF2),in the presence of 4-DPPC pretreatment during sinus rhythm, intravenousdipyridamole (2 to 3 mg) had no effect on heart rate or blood pressure(Table 2).

                  TABLE 1                                                         ______________________________________                                        Absence of an Effect of 4-DPPC on Current-Based                               Defibrillation Threshold                                                      ______________________________________                                        Control       vs.     4-DPPC                                                  28.1 ± 1.1A        26.4 ± 0.6 A (NS, N = 5)                             Control       vs.     Placebo                                                 30.9 ± 1.4         29.2 ± 1.9 A (NS, N = 5)                             ______________________________________                                         NS = No significant difference. All values expressed as mean ± standar     error of the mean.                                                       

                  TABLE 2                                                         ______________________________________                                        4-DPPC-Induced Attenuation of Post-defibrillation                             Electrophysiologic Depression                                                 PROTOCOL NO. 1                                                                       FSC     FSC       SSC       SSC                                               Pre ANT Post ANT  Pre ANT   Post ANT                                   ______________________________________                                        PR (msec)                                                                              143.8 ±                                                                              102.5* ±                                                                             167.4 ±                                                                            103.0* ±                                       9.0       2.5       11.6    2.3                                      SCL (msec)                                                                             447.5 ±                                                                              360.0* ±                                                                             487.4 ±                                                                            385.4* ±                                       9.5       8.2       22.8    10.0                                     Mean CL 1-3                  2637.8 ±                                                                           930.2* ±                              (msec)                       385.5   222.9                                    No. of beats                 14.2 ±                                                                             33.2* ±                               (15 secs)                    3.2     1.9                                      ______________________________________                                         Abbreviations:                                                                FSC, first shock conversions;                                                 SSC, second shock conversions;                                                ANT, antagonist (i.e. 4DPPC);                                                 Pr, PR interval noted at the 10th beat postdefibrillation;                    SCL, sinus cycle length noted at the 10th beat postdefibrillation;            mean CL 1-3, mean cycle length of the first 3 beats postdefibrillation.       *p < 0.02 vs. Pre ANT, N = 5.                                            

                                      TABLE 3                                     __________________________________________________________________________    4-DPPC-Induced Reversal of Post-Defibrillation Electrophysiologic             and Hemodynamic Depression in the Presence of Dipyridamole                    PROTOCOL NO. 2                                                                                  Pre VF1     Post Shock-                                                                         Post Shock-                                                                         Pre VF2                                                                              Pre VF2                      Pre MET     Post MET                                                                            Post DPM                                                                            VF1   Pre ANT                                                                             Post ANT                                                                            ANT    ANT + DPM                                                                             VF2                  __________________________________________________________________________    CL (msec)                                                                           404.0 ±                                                                          472.0 608.0   ±            568.0 ±                                                                           571.2 ±                         13.3  39.3  40.8                    52.7   49.8                         AoP syst.                                                                           116.0 ±                                                                          135.0 117.00** ±           129.0 ±                                                                           137.5 ±                   (mmHg)                                                                              6.6   8.9   13.1                    12.0   16.5                         AoP diast.                                                                          85.2 ±                                                                           103.0 78.0** ±             96.3 ±                                                                            100.0 ±                   (mmHg)                                                                              8.0   7.0   13.1                    10.6   13.7                         AoP mean                                                                            98.0 ±                                                                           117.4 97.0** ±             112.0 ±                                                                           117.5 ±                   (mmHg)                                                                              7.8   7.6   11.7                    10.3   14.6                         RAP mean                                                                            7.6 ±                                                                            8.2** ±                                                                          10.2   ±             11.4 ±                                                                            9.8 ±                     (mmHg)                                                                              0.8   0.9   1.2                     1.3    1.2                          Heart Rate              43.2 ±                                                                           48.2° ±                                                                   111.2* ±          123.2* ±          (ppm)                   20.4  15.1  10.3                 8.4                  AoP syst.               58.0 ±                                                                           66.6° ±                                                                   113.0* ±          110.0* ±          (mmHg)                  17.2  17.5  12.0                 6.7                  AoP diast.              9.4   11.5  16.9                 8.2                  __________________________________________________________________________     Abbreviations:                                                                MET, Methoxamine;                                                             DPM, dipyridamole;                                                            ANT, antagonist (4DPPC);                                                      VF1, post first ventricular fibrillation episode (45 secs duration);          VF2, post second VF episode (45 secs duration);                               CL, cycle length;                                                             AoP, aortic pressure;                                                         syst., systolic;                                                              diast., diastolic,                                                            RAP, right atrial pressure;                                                   bpm, beats per minute.                                                        Values for VF1 and VF2 were obtained at 15 secs postdefibrillation.           Values for PostShock-Post-ANT were obtained 30 secs following the             intravenous injection of the 4DPPC.                                           *p < 0.02 vs. VF1;                                                            °no significant difference (p >  0.05) vs. VF1;                        .sup.  p <  0.03 vs. Pre MET;                                                 **no significant difference (p >  0.05) vs. Pre MET;                          N = 5.                                                                   

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

REFERENCES

1. Geddes, L. A., W. A. Tacker, J. Rosborough, P. Cabler, R. Chapman,and R. Rivera. 1976. The increased efficacy of high-energydefibrillation. Med. Biol. Eng. May 1076:330-333.

2 Lerman, B. B., H. Halperin, J. Tsitlik, K. Brin, C. Clark, and O. C.Deale. 1987. Relationship between canine transthoracic impedance anddefibrillation threshold. J. Clin. Invest. 80:797-803.

3. Daniels, W. W. 1983. Biostatistics: A Foundation for Analysis in theHealth Sciences. John Wiley & Sons, New York. 1-534.

What is claimed as new and desired to be secured by Letters patent ofthe United States is:
 1. A method of enhancing the efficacy ofcardiopulmonary resuscitation, comprising:administering to a human oranimal with post-resuscitation asystole or cardiac arrhythmia an amountof an adenosine antagonist sufficient to alleviate said asystole andcardiac arrhythmia wherein said antagonist competitively inhibitsadenosine or reduces the level of adenosine present in myocardial tissueand associated fluids.
 2. The method of claim 1, wherein said antagonistis a xanthine derivative or non-xanthine derivative.
 3. The method ofclaim 2, wherein said antagonist is a methylxanthine.
 4. The method ofclaim 3, wherein said methylxanthine is selected from the groupconsisting of 1,3,7-trimethylxanthine; 3,7-dimethylxanthine;1,3-dimethylxanthine; aminophylline; and 8-(p-sulfophenyl)theophylline.5. The method of claim 2, wherein said antagonist is a propylxanthine.6. The method of claim 2, wherein said antagonist is(E)-4-(1,2,3,6-tetrahydro-l,3-dimethyl-2,6-dioxo-9H-purin-8-yl)cinnamicacid or(E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-l,3-dipropyl-9H-purine-8-yl)cinnamicacid.
 7. The method of claim 2, wherein said antagonist is anon-xanthine derivative.
 8. The method of claim 7, wherein saidnon-xanthine derivative is selected from the group consisting ofimidazopyrimidine, pyrazolopyridine, etazolate, pyrazoloquinoline andtriazoloquinazoline.
 9. The method of claim 1, wherein said antagonistis administered in a dose of about 0.1-20 mg/kg.
 10. The method of claim9, wherein said antagonist is administered in a dosage of from about0.45-10 mg/kg.
 11. The method of claim 9, wherein said antagonist isadministered in a dosage of about 3-5 mg/kg.
 12. The method of claim 1,wherein said administration is selected from the group consisting ofintravenous injection, oral ingestion, local release and insertion of asuppository.
 13. The method of claim 12, wherein said administration isby intravenous injection.
 14. The method of claim 13, wherein saidintravenous injection is a continuous intravenous injection.
 15. Themethod of claim 14, wherein said continuous intravenous injection is ata rate of about 0.45 mg/kg/hr.
 16. The method of claim 1, wherein saidadministering occurs concurrently with an α-adrenergic, β-adrenergic ordopaminergic agent.
 17. The method of claim 16, wherein said adrenergicor dopaminergic agent is administered in a ratio of about 0.01:1.0 to1.0:0.01 relative to said antagonist.
 18. The method of claim 1, whereinsaid enhancing comprises enhancing the effectiveness of cardioversion,defibrillation, and cardiac pacing within the setting of resuscitation.19. A method for the treatment of post-resuscitation asystole,bradyarrhythmias, electro-mechanical dissociation, and hemodynamiccollapse, comprising:administering to a human or animal withpost-resuscitation asystole or cardiac arrhythmia an amount of anadenosine antagonist sufficient to alleviate said asystole and cardiacarrhythmia wherein said antagonist competitively inhibits adenosine orreduces the level of adenosine present in myocardial tissue andassociated fluids.
 20. The method of claim 19, wherein said antagonistis a xanthine derivative or a non-xanthine derivative.
 21. The method ofclaim 20, wherein said antagonist is a methylxanthine.
 22. The method ofclaim 21, wherein said methylxanthine is selected from the groupconsisting of 1,3,7-trimethylxanthine; 3,7-dimethylxanthine;1,3-dimethylxanthine; aminophylline; and 8-(p-sulfophenyl)theophylline.23. The method of claim 19, wherein said antagonist is a propylxanthine.24. The method of claim 23, wherein said propylxanthine is(E)-4-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purin-8-yl)cinnamicacid or(E)-4-(1,2,3,6-tetrahydro-2,6-dioxo-1,3-dipropyl-9H-purine-8-yl)cinnamicacid.
 25. The method of claim 20, wherein said antagonist is anon-xanthine derivative.
 26. The method of claim 25, wherein saidnon-xanthine is selected from the group consisting of imidazopyrimidine,pyrazolopyridine, etazolate, pyrazoloquinoline and triazoloquinazoline.27. The method of claim 19, wherein said antagonist is administered in adose of about 0.1-20 mg/Kg.
 28. The method of claim 27, wherein saidantagonist is administered in a dose of from about 0.45-10 mg/Kg. 29.The method of claim 27, wherein said antagonist is administered in adose of about 3-5 mg/Kg.
 30. The method of claim 19, wherein saidadministration is selected from the group consisting of intravenousinjection, oral ingestion, local release and insertion of a suppository.31. The method of claim 30, wherein said administration is byintravenous injection.
 32. The method of claim 31, wherein saidintravenous injection is a continuous intravenous injection.
 33. Themethod of claim 32, wherein said continuous intravenous injection is ata rate of about 0.45 mg/Kg/hr.
 34. The method of claim 19, wherein saidadministering occurs concurrently with an α-adrenergic, β-adrenergic ordopaminergic agent.
 35. The method of claim 34, wherein said adrenergicor dopaminergic agent is administered in a ratio of about 0.01:1.0 toabout 1.0-0.01 relative to said antagonist.